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Article ; Online: Batch-effect correction with sample remeasurement in highly confounded case-control studies.

Ye, Hanxuan / Zhang, Xianyang / Wang, Chen / Goode, Ellen L / Chen, Jun

Nature computational science

2023 Volume 3, Issue 8, Page(s) 709–719

Abstract: Batch effects are pervasive in biomedical studies. One approach to address the batch effects is repeatedly measuring a subset of samples in each batch. These remeasured samples are used to estimate and correct the batch effects. However, rigorous ... ...

Abstract	Batch effects are pervasive in biomedical studies. One approach to address the batch effects is repeatedly measuring a subset of samples in each batch. These remeasured samples are used to estimate and correct the batch effects. However, rigorous statistical methods for batch-effect correction with remeasured samples are severely underdeveloped. Here we developed a framework for batch-effect correction using remeasured samples in highly confounded case-control studies. We provided theoretical analyses of the proposed procedure, evaluated its power characteristics and provided a power calculation tool to aid in the study design. We found that the number of samples that need to be remeasured depends strongly on the between-batch correlation. When the correlation is high, remeasuring a small subset of samples is possible to rescue most of the power.
MeSH term(s)	Case-Control Studies ; Research Design
Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article
ISSN	2662-8457
ISSN (online)	2662-8457
DOI	10.1038/s43588-023-00500-8
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Article ; Online: Multiplex Immunofluorescence Image Quality Checking Using DAPI Channel-referenced Evaluation.

Jiang, Jun / Moore, Raymond / Jordan, Clarissa E / Guo, Ruifeng / Maus, Rachel L / Liu, Hongfang / Goode, Ellen / Markovic, Svetomir N / Wang, Chen

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2023 Volume 71, Issue 3, Page(s) 121–130

Abstract: Multiplex immunofluorescence (MxIF) images provide detailed information of cell composition and spatial context for biomedical research. However, compromised data quality could lead to research biases. Comprehensive image quality checking (QC) is ... ...

Abstract	Multiplex immunofluorescence (MxIF) images provide detailed information of cell composition and spatial context for biomedical research. However, compromised data quality could lead to research biases. Comprehensive image quality checking (QC) is essential for reliable downstream analysis. As a reliable and specific staining of cell nuclei, 4',6-diamidino-2-phenylindole (DAPI) signals were used as references for tissue localization and auto-focusing across MxIF staining-scanning-bleaching iterations and could potentially be reused for QC. To confirm the feasibility of using DAPI as QC reference, pixel-level DAPI values were extracted to calculate signal fluctuations and tissue content similarities in staining-scanning-bleaching iterations for identifying quality issues. Concordance between automatic quantification and human experts' annotations were evaluated on a data set consisting of 348 fields of view (FOVs) with 45 immune and tumor cell markers. Cell distribution differences between subsets of QC-pass vs QC-failed FOVs were compared to investigate the downstream effects. Results showed that 87.3% FOVs with tissue damage and 73.4% of artifacts were identified. QC-failed FOVs showed elevated regional gathering in cellular feature space compared with the QC-pass FOVs. Our results supported that DAPI signals could be used as references for MxIF image QC, and low-quality FOVs identified by our method must be cautiously considered for downstream analyses.
MeSH term(s)	Humans ; Indoles ; Neoplasms ; Fluorescent Antibody Technique
Chemical Substances	DAPI (47165-04-8) ; Indoles
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218208-7
ISSN	1551-5044 ; 0022-1554
ISSN (online)	1551-5044
ISSN	0022-1554
DOI	10.1369/00221554231161693
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Article ; Online: Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis.

Gersekowski, Kate / Na, Renhua / Alsop, Kathryn / Delahunty, Rachel / Goode, Ellen L / Cunningham, Julie M / Winham, Stacey J / Pharoah, Paul D P / Song, Honglin / Webb, Penelope M

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2024 Volume 33, Issue 4, Page(s) 586–592

Abstract: Background: Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of ... ...

Abstract	Background: Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. Methods: We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. Results: IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00-1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07-1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. Conclusions: Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. Impact: Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.
MeSH term(s)	Female ; Humans ; Pregnancy ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Mutation ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Risk Factors ; Smoking/adverse effects
Chemical Substances	BRCA1 Protein ; BRCA2 Protein
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-23-0984
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Article ; Online: Generating real-world evidence from unstructured clinical notes to examine clinical utility of genetic tests: use case in BRCAness.

Zhao, Yiqing / Weroha, Saravut J / Goode, Ellen L / Liu, Hongfang / Wang, Chen

BMC medical informatics and decision making

2021 Volume 21, Issue 1, Page(s) 3

Abstract: Background: Next-generation sequencing provides comprehensive information about individuals' genetic makeup and is commonplace in oncology clinical practice. However, the utility of genetic information in the clinical decision-making process has not ... ...

Abstract	Background: Next-generation sequencing provides comprehensive information about individuals' genetic makeup and is commonplace in oncology clinical practice. However, the utility of genetic information in the clinical decision-making process has not been examined extensively from a real-world, data-driven perspective. Through mining real-world data (RWD) from clinical notes, we could extract patients' genetic information and further associate treatment decisions with genetic information. Methods: We proposed a real-world evidence (RWE) study framework that incorporates context-based natural language processing (NLP) methods and data quality examination before final association analysis. The framework was demonstrated in a Foundation-tested women cancer cohort (N = 196). Upon retrieval of patients' genetic information using NLP system, we assessed the completeness of genetic data captured in unstructured clinical notes according to a genetic data-model. We examined the distribution of different topics regarding BRCA1/2 throughout patients' treatment process, and then analyzed the association between BRCA1/2 mutation status and the discussion/prescription of targeted therapy. Results: We identified seven topics in the clinical context of genetic mentions including: Information, Evaluation, Insurance, Order, Negative, Positive, and Variants of unknown significance. Our rule-based system achieved a precision of 0.87, recall of 0.93 and F-measure of 0.91. Our machine learning system achieved a precision of 0.901, recall of 0.899 and F-measure of 0.9 for four-topic classification and a precision of 0.833, recall of 0.823 and F-measure of 0.82 for seven-topic classification. We found in result-containing sentences, the capture of BRCA1/2 mutation information was 75%, but detailed variant information (e.g. variant types) is largely missing. Using cleaned RWD, significant associations were found between BRCA1/2 positive mutation and targeted therapies. Conclusions: In conclusion, we demonstrated a framework to generate RWE using RWD from different clinical sources. Rule-based NLP system achieved the best performance for resolving contextual variability when extracting RWD from unstructured clinical notes. Data quality issues such as incompleteness and discrepancies exist thus manual data cleaning is needed before further analysis can be performed. Finally, we were able to use cleaned RWD to evaluate the real-world utility of genetic information to initiate a prescription of targeted therapy.
MeSH term(s)	Data Accuracy ; Electronic Health Records ; Female ; Humans ; Language ; Machine Learning ; Natural Language Processing
Language	English
Publishing date	2021-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1472-6947
ISSN (online)	1472-6947
DOI	10.1186/s12911-020-01364-y
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Article ; Online: Gene-based mediation analysis in epigenetic studies.

Fang, Ruiling / Yang, Haitao / Gao, Yuzhao / Cao, Hongyan / Goode, Ellen L / Cui, Yuehua

Briefings in bioinformatics

2020 Volume 22, Issue 3

Abstract: Mediation analysis has been a useful tool for investigating the effect of mediators that lie in the path from the independent variable to the outcome. With the increasing dimensionality of mediators such as in (epi)genomics studies, high-dimensional ... ...

Abstract	Mediation analysis has been a useful tool for investigating the effect of mediators that lie in the path from the independent variable to the outcome. With the increasing dimensionality of mediators such as in (epi)genomics studies, high-dimensional mediation model is needed. In this work, we focus on epigenetic studies with the goal to identify important DNA methylations that act as mediators between an exposure disease outcome. Specifically, we focus on gene-based high-dimensional mediation analysis implemented with kernel principal component analysis to capture potential nonlinear mediation effect. We first review the current high-dimensional mediation models and then propose two gene-based analytical approaches: gene-based high-dimensional mediation analysis based on linearity assumption between mediators and outcome (gHMA-L) and gene-based high-dimensional mediation analysis based on nonlinearity assumption (gHMA-NL). Since the underlying true mediation relationship is unknown in practice, we further propose an omnibus test of gene-based high-dimensional mediation analysis (gHMA-O) by combing gHMA-L and gHMA-NL. Extensive simulation studies show that gHMA-L performs better under the model linear assumption and gHMA-NL does better under the model nonlinear assumption, while gHMA-O is a more powerful and robust method by combining the two. We apply the proposed methods to two datasets to investigate genes whose methylation levels act as important mediators in the relationship: (1) between alcohol consumption and epithelial ovarian cancer risk using data from the Mayo Clinic Ovarian Cancer Case-Control Study and (2) between childhood maltreatment and comorbid post-traumatic stress disorder and depression in adulthood using data from the Gray Trauma Project.
MeSH term(s)	Adult ; Alcohol Drinking/genetics ; Child, Preschool ; Computer Simulation ; DNA Methylation ; Depression/genetics ; Epigenesis, Genetic ; Female ; Humans ; Male ; Mediation Analysis ; Models, Genetic ; Ovarian Neoplasms/genetics ; Stress Disorders, Post-Traumatic/genetics
Language	English
Publishing date	2020-06-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2068142-2
ISSN	1477-4054 ; 1467-5463
ISSN (online)	1477-4054
ISSN	1467-5463
DOI	10.1093/bib/bbaa113
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Article ; Online: Epigenetics in ovarian cancer.

Natanzon, Yanina / Goode, Ellen L / Cunningham, Julie M

Seminars in cancer biology

2017 Volume 51, Page(s) 160–169

Abstract: Ovarian cancer is a disease with a poor prognosis and little progress has been made to improve treatment. It is now recognized that there are several histotypes of ovarian cancer, each with distinct epidemiologic and genomic characteristics. Cancer ... ...

Abstract	Ovarian cancer is a disease with a poor prognosis and little progress has been made to improve treatment. It is now recognized that there are several histotypes of ovarian cancer, each with distinct epidemiologic and genomic characteristics. Cancer therapy is moving beyond classical chemotherapy to include epigenetic approaches. Epigenetics is the dynamic regulation of gene expression by DNA methylation and histone post translational modification in response to environmental cues. Improvement in technology to study DNA methylation has enabled a more agnostic approach and, with larger samples sets, has begun to unravel how epigenetics contributes to the etiology, response to chemotherapy and prognosis in of ovarian cancer. Investigations into histone modifications in ovarian cancer are more nascent. Much more is needed to be done to fully realize the potential that epigenetics holds for ovarian cancer clinical care.
MeSH term(s)	Animals ; DNA Methylation ; Epigenesis, Genetic ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology
Language	English
Publishing date	2017-08-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2017.08.003
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Article ; Online: Frequent POLE-driven hypermutation in ovarian endometrioid cancer revealed by mutational signatures in RNA sequencing.

Davila, Jaime I / Chanana, Pritha / Sarangi, Vivekananda / Fogarty, Zachary C / Weroha, S John / Guo, Ruifeng / Goode, Ellen L / Huang, Yajue / Wang, Chen

BMC medical genomics

2021 Volume 14, Issue 1, Page(s) 165

Abstract: Background: DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly ... ...

Abstract	Background: DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC. Methods: Mutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10. Results: In the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e-04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations. Conclusions: From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.
MeSH term(s)	Carcinoma, Endometrioid
Language	English
Publishing date	2021-06-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-021-01017-7
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Article: Testing Mediation Effects in High-Dimensional Epigenetic Studies.

Gao, Yuzhao / Yang, Haitao / Fang, Ruiling / Zhang, Yanbo / Goode, Ellen L / Cui, Yuehua

Frontiers in genetics

2019 Volume 10, Page(s) 1195

Abstract: Mediation analysis has been a powerful tool to identify factors mediating the association between exposure variables and outcomes. It has been applied to various genomic applications with the hope to gain novel insights into the underlying mechanism of ... ...

Abstract	Mediation analysis has been a powerful tool to identify factors mediating the association between exposure variables and outcomes. It has been applied to various genomic applications with the hope to gain novel insights into the underlying mechanism of various diseases. Given the high-dimensional nature of epigenetic data, recent effort on epigenetic mediation analysis is to first reduce the data dimension by applying high-dimensional variable selection techniques, then conducting testing in a low dimensional setup. In this paper, we propose to assess the mediation effect by adopting a high-dimensional testing procedure which can produce unbiased estimates of the regression coefficients and can properly handle correlations between variables. When the data dimension is ultra-high, we first reduce the data dimension from ultra-high to high by adopting a sure independence screening (SIS) method. We apply the method to two high-dimensional epigenetic studies: one is to assess how DNA methylations mediate the association between alcohol consumption and epithelial ovarian cancer (EOC) status; the other one is to assess how methylation signatures mediate the association between childhood maltreatment and post-traumatic stress disorder (PTSD) in adulthood. We compare the performance of the method with its counterpart
Language	English
Publishing date	2019-11-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2019.01195
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Article: Exome sequencing identifies

medRxiv : the preprint server for health sciences

2024

Abstract: Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to ... ...

Abstract	Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.02.24304968
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Article ; Online: Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.

Wang, Xuemin / Kho, Pik Fang / Ramachandran, Dhanya / Bafligil, Cemsel / Amant, Frederic / Goode, Ellen L / Scott, Rodney J / Tomlinson, Ian / Evans, D Gareth / Crosbie, Emma J / Dörk, Thilo / Spurdle, Amanda B / Glubb, Dylan M / O'Mara, Tracy A

iScience

2023 Volume 26, Issue 5, Page(s) 106590

Abstract: To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and ... ...

Abstract	To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106590
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